Identifying cellular and molecular signatures from distinct T cell receptor clonotypes associated with favorable immune checkpoint inhibitor responses in HNSCCs
识别与 HNSCC 中有利的免疫检查点抑制剂反应相关的不同 T 细胞受体克隆型的细胞和分子特征
基本信息
- 批准号:10573334
- 负责人:
- 金额:$ 68.14万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-03-01 至 2027-02-28
- 项目状态:未结题
- 来源:
- 关键词:Adjuvant StudyAftercareAntibodiesBloodCD8-Positive T-LymphocytesCD8B1 geneCancer PatientCancer PrognosisCarcinogensCellsCellular Indexing of Transcriptomes and Epitopes by SequencingClinicalClinical TrialsClonal ExpansionCombination immunotherapyCoupledDataDiseaseFutureHead and Neck Squamous Cell CarcinomaHumanHuman PapillomavirusImmune checkpoint inhibitorInstitutionLinkModelingMolecular ProfilingMusNeoadjuvant TherapyNivolumabPathway interactionsPatientsPeripheralPeripheral Blood LymphocytePhenotypePopulationPublishingResectableSamplingSplenocyteSurrogate MarkersT cell receptor repertoire sequencingT cell responseT-Cell ReceptorT-LymphocyteT-cell receptor repertoireTestingTumor AntigensTumor ExpansionTumor ImmunityTumor-Infiltrating LymphocytesValidationanti-CTLA4anti-PD-1anti-PD-L1anti-PD-L1 therapyantigen-specific T cellscancer immunotherapycancer typecheckpoint therapyimprovedinsightminimally invasivemolecular markermouse modelnovelprogrammed cell death protein 1responsesingle-cell RNA sequencingtranscriptometranscriptomicstumor
项目摘要
Project Summary/Abstract
Cancer immunotherapy has become one of the pillar therapies in treating cancer patients, exemplified by
immune checkpoint inhibitors (ICI) (e.g., anti-PD1). While ICIs have significantly improved the prognosis of
cancer patients, the response rate to ICI monotherapy remains low (10-20%) for many types of cancer, such as
head and neck squamous cell carcinoma (HNSCC). Some variability may be explained by human papillomavirus
(HPV)- vs. carcinogen-induced, tumor antigen-specific T cell responses in HPV+ or HPV− HNSCC, reflecting a
unique disease opportunity to investigate ICI responsiveness. Thus, it is vital to better understand the
mechanisms underlying heterogenous responses to ICI and to identify new targets that may sensitize HNSCCs
to mono- and combination immunotherapy. In this application, we propose to focus on T cell phenotypes
associated with clinical response, dynamic changes in specific T cell receptor (TCR) clonotypes, and TCR
clonotype-specific transcriptomic changes in response to ICI treatment, using HNSCC patient samples from an
ongoing clinical trial at our institution and detailed studies using murine HNSCC models. Using HCC 18-139 trial
samples, we will compare tumor infiltrating lymphocytes (TIL) and peripheral blood lymphocytes (PBL) from pre-
and post-treatment samples and examine TCR dynamics and T cell phenotypes in blood (minimally invasive and
readily accessible) and in tumors in the context of ICI-induced anti-tumor immunity. Our mouse model allows
functional validation among distinct TCR clonotypes correlating with ICI responses, and permits manipulation of
novel potential targets to enhance clinical responsiveness as well as lay the groundwork for future clinical trials.
Our proposed studies will identify cellular and molecular markers to better predict ICI responses in HNSCC
patients treated with different combinations of ICIs and would facilitate finding novel mechanisms of differential
ICI responses using transcriptomic differences in distinct clonal TCR-bearing T cell populations. A unique
strength of our proposal is integration of human clinical trial samples and mouse models as a more powerful
platform to uncover mechanistic insights that are translatable into the clinical setting.
项目摘要/摘要
癌症免疫疗法已成为治疗癌症患者的支柱疗法之一,例如
免疫检查点抑制物(ICI)(例如,抗PD1)。而ICIS显著改善了患者的预后
对于癌症患者,对于许多类型的癌症,ICI单一疗法的应答率仍然很低(10%-20%),例如
头颈部鳞癌(HNSCC)。一些变异可以用人类乳头瘤病毒来解释
在HPV+或HPV−人非小细胞癌中,HPV-与致癌物诱导的肿瘤抗原特异性T细胞反应,反映了
调查ICI响应性的独特疾病机会。因此,更好地理解
ICI异质性反应的潜在机制和识别可能使HNSCCs增敏的新靶点
单一免疫疗法和联合免疫疗法。在本应用中,我们建议重点研究T细胞表型
与临床反应、特异性T细胞受体(TCR)克隆型和TCR的动态变化相关
使用HNSCC患者样本对ICI治疗的反应的克隆型特异性转录变化
我们机构正在进行临床试验,并使用小鼠HNSCC模型进行详细研究。使用肝细胞癌18-139试验
样本,我们将比较肿瘤浸润性淋巴细胞(TIL)和外周血淋巴细胞(PBL)
并检测血液中TCR动态和T细胞表型(微创和
容易获取)和在ICI诱导的抗肿瘤免疫的背景下的肿瘤中。我们的鼠标模型允许
与ICI反应相关的不同TCR克隆类型之间的功能验证,并允许操纵
新的潜在目标,以提高临床响应性以及为未来的临床试验奠定基础。
我们建议的研究将确定细胞和分子标志物,以更好地预测HNSCC的ICI反应
患者接受不同的ICIS组合治疗,将有助于发现新的分化机制
ICI反应利用不同克隆性携带TCR的T细胞群体的转录差异。独一无二的
我们建议的优点是将人类临床试验样本和小鼠模型整合为更强大的
揭示可转化为临床环境的机械性见解的平台。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Robert L. Ferris其他文献
Perspectives in immunotherapy: meeting report from the “Immunotherapy Bridge 2018” (28–29 November, 2018, Naples, Italy)
- DOI:
10.1186/s40425-019-0798-3 - 发表时间:
2019-11-29 - 期刊:
- 影响因子:10.600
- 作者:
Paolo A. Ascierto;Carlo Bifulco;Luigi Buonaguro;Leisha A. Emens;Robert L. Ferris;Bernard A. Fox;Greg M. Delgoffe;Jérôme Galon;Cesare Gridelli;Marco Merlano;Paul Nathan;Kunle Odunsi;Hideho Okada;Chrystal M. Paulos;Sandro Pignata;Kurt A. Schalper;Stefani Spranger;Giampaolo Tortora;Hassane Zarour;Lisa H. Butterfield;Igor Puzanov - 通讯作者:
Igor Puzanov
31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016): late breaking abstracts
- DOI:
10.1186/s40425-016-0191-4 - 发表时间:
2016-12-01 - 期刊:
- 影响因子:10.600
- 作者:
Sonja Althammer;Keith Steele;Marlon Rebelatto;Tze Heng Tan;Tobias Wiestler;Guenter Schmidt;Brandon Higgs;Xia Li;Li Shi;Xiaoping Jin;Joyce Antal;Ashok Gupta;Koustubh Ranade;Gerd Binning;Joaquim Bellmunt;Ronald de Wit;David J. Vaughn;Yves Fradet;Jae Lyun Lee;Lawrence Fong;Nicholas J. Vogelzang;Miguel A. Climent;Daniel P. Petrylak;Toni K. Choueiri;Andrea Necchi;Winald Gerritsen;Howard Gurney;David I. Quinn;Stéphane Culine;Cora N. Sternberg;Yabing Mai;Markus Puhlmann;Rodolfo F. Perini;Dean F. Bajorin;Padmanee Sharma;Margaret K. Callahan;Emiliano Calvo;Joseph W. Kim;Filipo de Braud;Patrick A. Ott;Petri Bono;Rathi N. Pillai;Michael Morse;Dung T. Le;Matthew Taylor;Pavlina Spilliopoulou;Johanna Bendell;Dirk Jaeger;Emily Chan;Scott J. Antonia;Paolo A. Ascierto;Delphine Hennicken;Marina Tschaika;Alex Azrilevich;Jonathan Rosenberg;Ofer Levy;Christopher Chan;Gady Cojocaru;Spencer Liang;Eran Ophir;Sudipto Ganguly;Amir Toporik;Maya Kotturi;Tal Fridman Kfir;Benjamin M. Murter;Kathryn Logronio;Liat Dassa;Ling Leung;Shirley Greenwald;Meir Azulay;Sandeep Kumar;Zoya Alteber;Xiaoyu Pan;Arthur Machlenkin;Yair Benita;Andrew W. Drake;Ayelet Chajut;Ran Salomon;Ilan Vankin;Einav Safyon;John Hunter;Zurit Levine;Mark White;Rom Leidner;Hyunseok Kang;Robert Haddad;Neil H. Segal;Lori J. Wirth;Robert L. Ferris;F. Stephen Hodi;Rachel E. Sanborn;Thomas F. Gajewski;William Sharfman;Dan McDonald;Shivani Srivastava;Xuemin Gu;Penny Phillips;Chaitali Passey;Tanguy Seiwert;Tsadik Habtetsion;Gang Zhou;Donastas Sakellariou-Thompson;Cara Haymaker;Caitlin Creasy;Mark Hurd;Naohiro Uraoka;Jaime Rodriguez Canales;Scott Koptez;Patrick Hwu;Anirban Maitra;Chantale Bernatchez;Scott M. Coyle;Kole T. Roybel;Levi J. Rupp;Stephen P. Santoro;Stephanie Secrest;Michael Spelman;Hanson Ho;Tina Gomes;Tiffany Tse;Chia Yung-Wu;Jack Taunton;Wendell Lim;Peter Emtage;Tarsem Moudgil;Carmen Ballesteros-Merino;Traci Hilton;Christopher Paustian;Rom Leidner;David Page;Walter Urba;Bernard Fox;Bryan Bell;Ashish Patel;Tove Olafsen;Daulet Satpayev;Michael Torgov;Filippo Marchioni;Jason Romero;Ziyue Karen Jiang;Charles Zamilpa;Jennifer S. Keppler;Alessandro Mascioni;Fang Jia;Chen-Yu Lee;Jean Gudas;Ryan J. Sullivan;Yujin Hoshida;Theodore Logan;Nikhil Khushalani;Anita Giobbie-Hurder;Kim Margolin;Joanna Roder;Rupal Bhatt;Henry Koon;Thomas Olencki;Thomas Hutson;Brendan Curti;Shauna Blackmon;James W. Mier;Igor Puzanov;Heinrich Roder;John Stewart;Asim Amin;Marc S. Ernstoff;Joseph I. Clark;Michael B. Atkins;Howard L. Kaufman;Jeffrey Sosman;Sabina Signoretti;David F. McDermott;Abraham A. Anderson;Igor Puzanov;Mohammed M. Milhem;Robert H. I. Andtbacka;David Minor;Kevin S. Gorski;Daniel M. Baker;Omid Hamid;Howard L. Kaufman;Emmanuel Akporiaye;Brendan Curti;Yoshinobu Koguchi;Rom Leidner;Kim Sutcliffe;Kristie Conder;Walter Urba;Thomas Marron;Nina Bhardwaj;Linda Hammerich;Fiby George;Seunghee Kim-Schulze;Tibor Keler;Tom Davis;Elizabeth Crowley;Andres Salazar;Joshua Brody;Arta Monjazeb;Megan E. Daly;Jonathan Riess;Tianhong Li;William J. Murphy;Karen Kelly;Zhiwei Hu;Rulong Shen;Amanda Campbell;Elizabeth McMichael;Lianbo Yu;Bhuvaneswari Ramaswam;Cheryl A. London;Tian Xu;William Carson;Kathleen M. Kokolus;Elizabeth A. Repasky;Todd D. Schell;Joseph D. Drabick;David J. Messenheimer;Shawn Jensen;Bernard Fox;Mark Rubinstein;Kristina Andrijauskaite;Marzena Swiderska-syn;Kristin Lind;Agnes Choppin;Marina K. Roell;John Wrangle;Kristina Andrijauskaite;Marzena Swiderska-syn;Peter Rhode;Hing Wong;Mark Rubinstein;Shamim Ahmad;Mason Webb;Rasha Abu-Eid;Rajeev Shrimali;Vivek Verma;Atbin Doroodchi;Zuzana Berrong;David Yashar;Raed Samara;Mikayel Mkrtichyan;Samir Khleif;Steven Powell;Mark Gitau;Christopher Sumey;Andrew Terrell;Michele Lohr;Ryan K. Nowak;Steven McGraw;Ash Jensen;Miran Blanchard;Kathryn A. Gold;Ezra E. W. Cohen;Christie Ellison;Lora Black;John Lee;William Chad Spanos;Erik Wennerberg;Emily Schwitzer;Claire Lhuillier;Graeme Koelwyn;Rebecca Hiner;Lee Jones;Sandra Demaria;Vandeveer Amanda;John W. Greiner;Jeffrey Schlom;Michelle Bookstaver;Christopher M. Jewell;Christopher Paustian;Andrew Gunderson;Brian Boulmay;Rui Li;Bradley Spieler;Kyle Happel;Tarsem Moudgil;Zipei Feng;Carmen Ballesteros-Merino;Christopher Dubay;Brenda Fisher;Yoshinobu Koguchi;Sandra Aung;Eileen Mederos;Carlo B. Bifulco;Michael McNamara;Keith Bahjat;William Redmond;Augusto Ochoa;Hong-Ming Hu;Adi Mehta;Fridtjof Lund-Johansen;Bernard Fox;Walter Urba;Rachel E. Sanborn;Traci Hilton;Frank Bedu-Addo;Greg Conn;Michael King;Panna Dutta;Robert Shepard;Mark Einstein;Sylvia Adams;Ena Wang;Ping Jin;Yelena Novik;Debra Morrison;Ruth Oratz;Franco M. Marincola;David Stroncek;Judith Goldberg;Sandra Demaria;Silvia C. Formenti;Jérôme Galon;Bernhard Mlecnik;Florence Marliot;Fang-Shu Ou;Carlo B. Bifulco;Alessandro Lugli;Inti Zlobec;Tilman T. Rau;Iris D. Nagtegaal;Elisa Vink-Borger;Arndt Hartmann;Carol Geppert;Michael H. Roehrl;Prashant Bavi;Pamela S. Ohashi;Julia Y. Wang;Linh T. Nguyen;SeongJun Han;Heather L. MacGregor;Sara Hafezi-Bakhtiari;Bradley G. Wouters;Yutaka Kawakami;Boryana Papivanova;Mingli Xu;Tomonobu Fujita;Shoichi Hazama;Nobuaki Suzuki;Hiroaki Nagano;Kiyotaka Okuno;Kyogo Itoh;Eva Zavadova;Michal Vocka;Jan Spacek;Lubos Petruzelka;Bohuslav Konopasek;Pavel Dundr;Helena Skalova;Toshihiko Torigoe;Noriyuki Sato;Tomohisa Furuhata;Ichiro Takemasa;Marc Van den Eynde;Anne Jouret-Mourin;Jean-Pascal Machiels;Tessa Fredriksen;Lucie Lafontaine;Bénédicte Buttard;Sarah Church;Pauline Maby;Helen Angell;Mihaela Angelova;Angela Vasaturo;Gabriela Bindea;Anne Berger;Christine Lagorce;Prabhu S. Patel;Hemangini H. Vora;Birva Shah;Jayendrakumar B. Patel;Kruti N. Rajvik;Shashank J. Pandya;Shilin N. Shukla;Yili Wang;Guanjun Zhang;Giuseppe V. Masucci;Emilia K. Andersson;Fabio Grizzi;Luigi Laghi;Gerardo Botti;Fabiana Tatangelo;Paolo Delrio;Gennaro Cilberto;Paolo A. Ascierto;Franco Marincola;Daniel J. Sargent;Bernard A. Fox;Alain Algazi;Katy Tsai;Michael Rosenblum;Prachi Nandoskar;Robert H. I. Andtbacka;Amy Li;John Nonomura;Kathryn Takamura;Mary Dwyer;Erica Browning;Reneta Talia;Chris Twitty;Sharron Gargosky;Jean Campbell;Carmen Ballesteros-Merino;Carlo B. Bifulco;Bernard Fox;Mai Le;Robert H. Pierce;Adil Daud;Robyn Gartrell;Douglas Marks;Edward Stack;Yan Lu;Daisuke Izaki;Kristen Beck;Dan Tong Jia;Paul Armenta;Ashley White-Stern;Yichun Fu;Zoe Blake;Howard L. Kaufman;Bret Taback;Basil Horst;Yvonne M. Saenger;Steven Leonardo;Keith Gorden;Ross B. Fulton;Kathryn Fraser;Takashi O. Kangas;Richard Walsh;Kathleen Ertelt;Jeremy Graff;Mark Uhlik;Jennifer S. Sims;Liang Lei;Takashi Tsujiuchi;Jeffrey N. Bruce;Peter Canoll;Anthony W Tolcher;Evan W Alley;Gurunadh Chichili;Jan E Canoll;Paul Moore;Ezio Bonvini;Syd Johnson;Sadhna Shankar;James Vasselli;Jon Wigginton;John Powderly - 通讯作者:
John Powderly
The great debate at “Immunotherapy Bridge 2018”, Naples, November 29th, 2018
- DOI:
10.1186/s40425-019-0683-0 - 发表时间:
2019-08-15 - 期刊:
- 影响因子:10.600
- 作者:
Paolo A. Ascierto;Lisa H. Butterfield;Sandra Demaria;Robert L. Ferris;Gordon J. Freeman;Roger S. Lo;Alberto Mantovani;Paul Nathan;Omid Hamid;Katerina Politi;Igor Puzanov - 通讯作者:
Igor Puzanov
The changing therapeutic landscape of head and neck cancer
头颈部癌症治疗领域的变化
- DOI:
10.1038/s41571-019-0227-z - 发表时间:
2019-06-12 - 期刊:
- 影响因子:82.200
- 作者:
John D. Cramer;Barbara Burtness;Quynh Thu Le;Robert L. Ferris - 通讯作者:
Robert L. Ferris
Functional laryngeal dyskinesia: A 17-year experience
- DOI:
10.1016/s0194-5998(97)80335-x - 发表时间:
1997-08-01 - 期刊:
- 影响因子:
- 作者:
Robert L. Ferris;David Tunkel;D.W. Eisele - 通讯作者:
D.W. Eisele
Robert L. Ferris的其他文献
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{{ truncateString('Robert L. Ferris', 18)}}的其他基金
Mechanisms of PD-1 and Tim-3 crosstalk in tumor-infiltrating lymphocytes
肿瘤浸润淋巴细胞中 PD-1 和 Tim-3 串扰的机制
- 批准号:
9898328 - 财政年份:2016
- 资助金额:
$ 68.14万 - 项目类别:
Mechanisms of PD-1 and Tim-3 crosstalk in tumor-infiltrating lymphocytes
肿瘤浸润淋巴细胞中 PD-1 和 Tim-3 串扰的机制
- 批准号:
9250721 - 财政年份:2016
- 资助金额:
$ 68.14万 - 项目类别:
Mechanisms of PD-1 and Tim-3 crosstalk in tumor-infiltrating lymphocytes
肿瘤浸润淋巴细胞中 PD-1 和 Tim-3 串扰的机制
- 批准号:
10745167 - 财政年份:2016
- 资助金额:
$ 68.14万 - 项目类别:
Immune activation by cetuximab in head and neck cancer patients
西妥昔单抗对头颈癌患者的免疫激活作用
- 批准号:
8289554 - 财政年份:2010
- 资助金额:
$ 68.14万 - 项目类别:
Immune activation by cetuximab in head and neck cancer patients
西妥昔单抗对头颈癌患者的免疫激活作用
- 批准号:
8685765 - 财政年份:2010
- 资助金额:
$ 68.14万 - 项目类别:
Immune activation by cetuximab in head and neck cancer patients
西妥昔单抗对头颈癌患者的免疫激活作用
- 批准号:
8705630 - 财政年份:2010
- 资助金额:
$ 68.14万 - 项目类别:
Immune activation by cetuximab in head and neck cancer patients
西妥昔单抗对头颈癌患者的免疫激活作用
- 批准号:
8096694 - 财政年份:2010
- 资助金额:
$ 68.14万 - 项目类别:
Immune activation by cetuximab in head and neck cancer patients
西妥昔单抗对头颈癌患者的免疫激活作用
- 批准号:
8499285 - 财政年份:2010
- 资助金额:
$ 68.14万 - 项目类别:
Chemokine Signals in Head and Neck Cancer Progression
头颈癌进展中的趋化因子信号
- 批准号:
7098453 - 财政年份:2006
- 资助金额:
$ 68.14万 - 项目类别:
Chemokine Signals in Head and Neck Cancer Progression
头颈癌进展中的趋化因子信号
- 批准号:
7763909 - 财政年份:2006
- 资助金额:
$ 68.14万 - 项目类别:
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